Background and AimsAlpha-Gal Syndrome (AGS) is an IgE-mediated allergic reaction to galactose-α-1,3-galactose, primarily linked with lone star tick bites in the US. It presents with symptoms ranging from urticaria and gastrointestinal (GI) manifestations to delayed anaphylaxis following red meat consumption. We aimed to study AGS patients' clinical manifestations, diagnosis, and outcomes. MethodsA retrospective chart review of patients who underwent serological testing for suspected AGS between 2014-2023 at Mayo Clinic was performed. Patients with positive serology were age and sex-matched with those who tested negative. Clinical characteristics of seropositive cohort with and without GI symptoms were compared, and outcomes assessed. ResultsOf 1260 patients who underwent testing, 124 tested positive for AGS. They were matched with 380 seronegative controls. AGS patients reported a higher frequency of tick bites (OR 26.0 [95% CI 9.8-68.3]), prevalence of urticaria (56 % vs. 37%; P=.0008) and were less likely to have asthma (OR 0.4 [0.3 to 0.7]). They had a lower prevalence of heartburn (6% vs. 12%; P=.03) and bloating (6% vs. 13%; P=.03). 47% had GI symptoms and higher proportion were female than those without GI symptoms (69% vs. 35%; P=.002). During a mean follow up of 27 months, 22 of 40 patients reported symptom resolution after avoiding red meat, and 7 were able to transition to regular diet. ConclusionA diagnosis of AGS should be strongly considered in patients with a history of tick bites and clinical presentation of allergic or GI manifestations. Dietary intervention is effective in most but not all patients.